Identifying Vulnerable Plaque in Rheumatoid Arthritis Abstract It is well established that rheumatoid arthritis (RA) is associated with a higher risk of cardiovascular disease (CVD) and mortality, which is not explained by traditional CV risk factors alone. Furthermore, this CV mortality risk is higher among RA patients with higher degrees of systemic inflammation. It is known that systemic inflammation is also associated with atherosclerotic plaque vulnerability. RA-related differences in plaque vulnerability have not been extensively studied. Traditional imaging modalities fail to detect features of plaque vulnerability and have not been correlated with increased disease activity in RA, despite the known association between inflammation and disease activity on CVD risk in RA. Recently, increased neovascularization in vasa vasorum has been identified as a common feature of inflammation and plaque vulnerability, and has been found to be an independent predictor of future CV events. This suggests that excess CVD risk in RA may be caused by disease-related factors that lead to vulnerable atherosclerotic plaque characterized by increased neovascularization of vasa vasorum, which is not assessed by traditional imaging modalities. Accordingly, we hypothesize that RA patients are more likely than non-RA patients to develop vulnerable atherosclerotic plaques that are associated with acute CVD events. Microbubble contrast-enhanced carotid ultrasound (CU) is a novel imaging technique that has been validated in detecting measures of vulnerable plaque, namely increased adventitial vasa vasorum density. The Specific Aims of our proposal are: 1. To determine whether patients with RA have an increased density of carotid artery adventitial vasa vasorum compared to control subjects without RA, after controlling for CV risk factors. 2. To determine whether both traditional CV risk factors and inflammatory or RA-related modulators of plaque vulnerability are associated with increased density of carotid artery adventitial vasa vasorum, as assessed by CU. 3. To determine whether increased disease activity measures in RA are associated with increased density of carotid artery adventitial vasa vasorum, as assessed by CU. The proposed study will recruit RA subjects from the ongoing NIH-funded RA Comparative Effectiveness Research (RACER) study (PIs: Larry Moreland, MD and Marc Levesque, MD, PhD) at the University of Pittsburgh Medical Center (UPMC). The RACER study is a longitudinal study of RA patients, with systematic collection of disease activity indices, quality-of-life measures, and stored serum. Control subjects will be identified from low-risk subjects who have recently completed CU studies in the NIH-funded prospective longitudinal cohort study, Heart Strategies Concentrating On Risk Evaluation (Heart SCORE) (PI: Steven Reis, MD) at UPMC. Subjects will undergo the CU studies at the Vascular Clinical and Translational Research Center (VCTRC), which is a state-of-the-art vascular studies unit with technicians trained in comprehensive assessments of CU and other vascular studies in human subjects in research protocols through the Clinical and Translational Science Institute (CTSI). This rich institutional environment and Dr. Liang's assembled mentoring team of experts in RA (Dr. Moreland) and cardiology/vascular imaging (Drs. Reis, Villanueva, and Mulukutla) demonstrate the suitability of funding for this K23 Mentored Patient-Oriented Research Career Development Award. Dr. Liang is an ideal candidate to carry out the proposed investigation. She has previously completed research projects at the Mayo Clinic investigating the risk of CVD in RA under the mentorship of Drs. Sherine Gabriel and Eric Matteson. She has a strong track record of presenting and publishing work in the areas of premature atherosclerosis in the rheumatic diseases as well as in vasculitis. Her short- and long-term career goals include becoming proficient in the novel CU imaging technique as a means to study vulnerable plaque in the rheumatic diseases and in vasculitis, developing a longitudinal cohort of inflammatory vascular diseases for future multidisciplinary studies, and becoming an independent physician-scientist with expertise in vascular biology within the rheumatic diseases. The proposed work follows seamlessly along her prior contributions to the field of study in premature CVD in RA, with the innovative concept that persons with RA may develop more vulnerable atherosclerotic plaque, as visualized by the novel CU imaging technique, than persons without RA. The significant clinical implications of detecting subclinical vulnerable plaque in patients with RA include possible early CVD risk stratification and prevention strategies, to help lower the excess burden of clinical CVD events and mortality in this high-risk patient population. PUBLIC HEALTH RELEVANCE: Identifying Vulnerable Plaque in Rheumatoid Arthritis Project Narrative It is well established that rheumatoid arthritis (RA) is associated with a higher risk of cardiovascular disease (CVD) and mortality, which is not explained by traditional CVD risk factors alone. It is also known that widespread inflammation, like that experienced by RA patients, is also associated with a more vulnerable atherosclerotic plaque, which is more prone to rupture and result in CVD events like heart attacks. Moreover, RA-related differences in plaque vulnerability have not been extensively studied. Traditional imaging techniques, like carotid ultrasound without contrast, fail to detect plaque vulnerability. We will test a novel, innovative microbubble-enhanced contrast agent in detecting vulnerable plaque and understanding its role in CVD risk in the RA patient.